1. Field of the Invention
The present invention relates to 4'-acyl derivatives of 4'-demethylepipodophyllotoxin glucosides, to their use as antitumor agents, and to pharmaceutical compositions containing them. In particular, this invention relates to the 4'-ester, 4'-carbonates, and 4'-carbamates of 4'-demethylepipodophyllotoxin glucosides.
2. Description of Background Art
Etoposide (Ia) and teniposide (Ib) are clinically useful anti-tumor agents derived from the naturally occurring lignan, podophyllotoxin. The general class of compounds which includes etoposide and teniposide is sometimes referreed to as 4'-demethylepipodophyllotoxin glucosides; the 4'-position is indicated on formula (I) below. ##STR1##
4'-Demethylepipodophyllotoxin glucoside derivatives and the method for their preparation are disclosed in U.S. Pat. No. 3,408,441 to Wartburg et al and U.S. Pat. No. 3,524,844 to Keller-Juslen et al. These compounds, in particular etoposide and teniposide, serve as the starting materials for our preparation of the 4'-acyl derivatives of epipodophyllotoxin glucosides of the present invention.
A few 4'-esters and 4'-benzylcarbonates of 4'-demethylepipodophyllotoxin glucosides have been described in the literature as intermediates for the preparation of the corresponding 4'-demethylepipodophyllotoxin glucosides. However, the hydroxyl groups on the sugar moiety of these compounds are also protected and no biological activities have been reported therefor. Only one 4'-acyl derivative having free sugar hydroxyl groups has been reported.
Canadian Patent No. 956,939 discloses compounds of formula (II) ##STR2## wherein R.sup.1 is C.sub.1-5 alkyl; R.sup.2 is acetyl or formyl; and R.sup.3 is phenyl or substituted phenyl; possible substituted phenyls mentioned but not exemplified are p-nitrophenyl and p-methoxyphenyl. There is also disclosed the process of selectively removing the R.sup.2 groups of compounds of formula (III), wherein R.sup.1 and R.sup.2 are as above-defined, to give the corresponding 4'-benzyloxycarbonyl-4'-demethylepipodophyllotoxin glucosides (IV). Specifically exemplified is the preparation of 4'-benzyloxycarbonyl-4'-demethylepipodophyllotoxin-.beta.-D-ethylidene glucoside (IV, R.sup.1 =CH.sub.3). ##STR3##
U.S. Pat. No. 4,564,675 discloses compounds of the formula (V) ##STR4## wherein R is --C(O)CH.sub.2 X, X is a halogen atom.
European Patent Application 162,701 discloses compounds of formula (VI) ##STR5## wherein R.sup.1 and R.sup.2 may be the same or different and each represent --C(O)CHX.sub.2 or --C(O)CX.sub.3 wherein X is a halogen atom.
Japanese Kokai 58/225,096 (Derwent Abst. No. 84-034268/06) and 58/219,196 (Derwent Abst. No. 84-027495/05) disclose compounds of formula (VII) and (VIII), respectively. ##STR6## wherein A stands for --CO.sub.2 --CH.sub.2 --C(H)m(X)n wherein m is 0 to 2 and n is 1 to 3, m+n=3, and Ac is acetyl.
European Patent Application 226,202 discloses an intermediate for etoposide synthesis having the formula (IX) ##STR7## wherein A represents an acetyl group.
Esters of podophyllotoxin at the C-4 position (X) have been prepared and evaluated in P388 leukemeia. Although some esters showed antileukemic activity, they are nonetheless less active than the parent podophyllotoxin (J. Pharm. Sci., 1983, 72: 1158-61). ##STR8## R is for example, methyl, ethylene, phenyl, phenethyl, phenoxy, and ethoxycarbonylbutyl.
C-4 esters of 4'-demethylepipodophyllotoxin (XI) have also been prepared and studied in vitro. They were found to behave like podophyllotoxin as microtubule assembly inhibitors, and did not show etoposide/teniposide-like activity (Anti-Cancer Drug Design, 1987. 2: 13-23). ##STR9## R.sup.2 is H and R.sup.1 is for example methyl, phenyl, furyl; or R.sup.2 is benzyloxycarbonyl and R.sup.1 is 2-thienyl or 2,2-dimethylethylene.
It has now been discovered that surprisingly 4'-acyl-4'-demethylepipodophyllotoxin glucosides are potent antitumor agents in their own right and several 4'-acyl derivatives exhibit better activity than etoposide in the P388 leukemia model.